Human saliva is a very attractive body fluid for disease diagnostics because saliva testing has several key advantages including minimum cost, non-invasiveness, and easy sample collection and processing. In this application, we hypothesize that saliva from oral cancer patients contains signature proteins that can serve as biomarkers for highly sensitive and specific detection of oral cancer. Two specific aims are in place to test the hypothesis. Aim 1 is to engage a quantitative proteomics platform, iTRAQ and 2-D LC-MS/MS, to harness saliva signature proteins associated with human oral cancer. Aim 2 is to validate the candidate biomarkers discovered in Aim 1 and build multi-marker prediction models for oral cancer detection. Proof of principle and feasibility studies have been well demonstrated for all aspects of this application. The overarching goal of the proposal is to discover saliva protein biomarkers and then translate the proteomic discoveries into prediction models that can be used for clinical diagnosis of oral cancer. The novelty of the proposed studies lies in the utilization of an emerging proteomics technology to explore a new diagnostic system for cancer detection. The proposed studies will develop highly sensitive and specific saliva biomarkers for human oral cancer detection. It may lead to extensive use of saliva testing for oral cancer diagnosis in the future.